Cytotoxic metal chelators and methods for making and using same

Abstract

A family of hexadentate Fe(II) chelators having marked antiproliferative activity against tumor cells is disclosed. The cytotoxic metal chelators and complexes of the present invention are represented by the general formula below:wherein:X1, X3, and X5 are N, O or S, wherein the X1, X3, and X5 atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition;B, B', and B'' are aliphatic, branched aliphatic, or aryl groups, or any combination thereof, wherein the number of atoms between X and Y is about 2 to about 4;Y, Y' and Y'' contain N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, or heterocyclic groups, or any combination thereof, and/or Y, Y' and Y'' are NH2 or NHR, OH, or SH, CO2H, P(O)(OH)2, RP(O)OH, ROP(O)OH groups or a combination thereof, and R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Y, Y' and Y'';s, s', and s'' are 0 to about 2; andt, t', and t'' are 0 to about 2. Application of the metal chelators of the present invention as chemotherapeutic agents is also disclosed.

What is claimed is:  
     
       1. A family of hexadentate Fe(II) chelators, said Fe(II) chelators being represented by the formulas below:                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition;  
       B, B′, and B″ are aryl groups;  
       Y, Y′, and Y″ contain N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, or heterocyclic groups, or any combination thereof, and/or Y, Y′ and Y″ are NH 2  or NHR, OH, or SH, CO 2 H, P(O)(OH) 2 , RP(O)OH, ROP(O)OH groups or any combination thereof, and R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Y, Y′ and Y″;  
       s, s′, and s″ are 1 to about 2; and  
       t, t′, and t″ are 1 to about 2;                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition;  
       B, B′, and B″ are aryl groups;  
       Y, Y′ and Y″ contain N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, or heterocyclic groups, or any combination thereof, or NH 2  or NHR, OH, or SH, CO 2 H, P(O)(OH) 2 , RP(O)OH, ROP(O)OH groups or any combination thereof, and R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Y, Y′ and Y″;  
       t, t′, and t″ are 1 to about 2; and  
       n is between 0 and about 3;                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition; and  
       s, s′, s″ are 1 to about 2;                    
       wherein: 
       R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Z, Z′ and Z″;  
       Y is NH 2  or NHR′, OH, or SH, CO 2 H, P(O)(OH) 2 , R′P(O)OH, R′OP(O)OH groups, or any combination thereof, and R′ is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof, or Y is a group containing N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, heterocyclic groups, or any combination thereof, in any case, Y and R′ may or may not be identical in Z, Z′ and Z″;  
       t is 1 to about 2; and  
       n is between 0 and about 3.  
     
     
       2. The family of hexadentate Fe(II) chelators in accordance with  claim 1 , wherein the Fe(II) chelators are selected from the group consisting of tach-C(Me)pyr, tach-6-Mepyr, tachquin, s,s,s-tachem-2Bn, s,s,s-tachen-2Me, (N—R) 3 tachpry, tachpyr-2H 2  and tach-N-Me-Im-imine. 
     
     
       3. The family of hexadentate Fe(II) chelators in accordance with  claim 1 , wherein each chelator is formulated in a therapeutic dosage singly, in combination with at least one pharmaceutical or chemically linked to at least one pharmaceutical. 
     
     
       4. The family of hexadentate Fe(II) chelators in accordance with  claim 1 , wherein the chelators are each in combination with pharmaceutically acceptable carriers, diluents, stabilizers, solubilizers, lubricants, binders, or excipients. 
     
     
       5. The family of hexadentate Fe(II) chelators in accordance with  claim 1 , wherein the chelators exhibit antiproliferative activity against tumor cells. 
     
     
       6. A pharmaceutical composition for treating and preventing medical conditions in mammals, the composition being capable of binding intracellular iron and comprising as active ingredient a compound of the formula:                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition;  
       B, B′, and B″ are aryl groups;  
       Y, Y′ and Y″ contain N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, or heterocyclic groups, or a combination thereof, and/or Y, Y′ and Y″ are NH 2  or NHR, OH, or SH, CO 2 H, P(O)(OH) 2 , RP(O)OH, ROP(O)OH groups or a combination thereof, and R is H, aliphatic, branched aliphatic, or aryl groups, or a combination thereof that may or may not be identical in Y, Y′ and Y″;  
       s, s′, and s″ are 1 to about 2; and  
       t, t′, and t″ are 1 to about 2.  
     
     
       7. The pharmaceutical composition in accordance with  claim 6 , wherein the active ingredient compound is selected from the group of metal chelators consisting of tach-C(Me)pyr, tach-6-Mepyr, tachquin, sss-tachem-2Bn, sss-tachen-2Me, (N—R) 3 tachpyr, tachpyr-2H 2  and tach-N-Me-Im-imine. 
     
     
       8. The pharmaceutical composition in accordance with  claim 6 , wherein the composition is a chemotherapeutic agent. 
     
     
       9. The pharmaceutical composition in accordance with  claim 6 , wherein the composition is formulated in a therapeutic dosage by itself, in combination with at least one other pharmaceutical, or chemically linked to at least one other pharmaceutical. 
     
     
       10. The pharmaceutical composition in accordance with  claim 6 , wherein the composition is in combination with pharmaceutically acceptable carriers, diluents, stabilizers, solubilizers, lubricants, binders and the like or excipients thereof. 
     
     
       11. The pharmaceutical composition in accordance with  claim 6 , wherein the composition comprises a mammalian metabolic conjugate of the active ingredient compound. 
     
     
       12. The pharmaceutical composition in accordance with  claim 6 , wherein the medical conditions include, but are not limited to, cancer, inflammatory and infectious conditions, vasoreactive and vasoocclusive conditions, coronary and peripheral athlerosclerosis, parasitic diseases, neurologic and neuromuscular conditions, and viral conditions including AIDS. 
     
     
       13. The pharmaceutical composition in accordance with  claim 12 , wherein the medical conditions further include vasospasm, Parkinson's disease, Alzeihmer's disease, malaria, tuberculosis, arthritis, allergic and asthmatic conditions, hepatitis, coronary and peripheral vascular ischemia-reperfusion injury of blood vessels. 
     
     
       14. The pharmaceutical composition in accordance with  claim 6 , wherein the composition is orally formulated in combination with a liquid diluant or a solid carrier. 
     
     
       15. The pharmaceutical composition in accordance with  claim 6 , wherein the therapeutically effective dosage of the composition prevents the occurrence of, reduces the rate of growth of, or diminishes the size of tumor cells or any combination thereof. 
     
     
       16. A pharmaceutical composition for treating and preventing medical conditions in mammals, the composition being capable of binding intracellular iron and comprising as active ingredient a compound of the formula:                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition;  
       B, B′, and B″ are aryl groups;  
       Y, Y′ and Y″ contain N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, or heterocyclic groups, or any combination thereof, or NH 2  or NHR, OH, or SH, CO 2 H, P(O)(OH) 2 , RP(O)OH, ROP(O)OH groups or any combination thereof, and R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Y, Y′ and Y″;  
       t, t′, and t″ are 1 to about 2; and  
       n is between 0 and about 3.  
     
     
       17. The pharmaceutical composition in accordance with  claim 16 , wherein the active ingredient compound is selected from the group of metal chelators consisting of sss-tachen-2Bn and sss-tachen-2Me. 
     
     
       18. The pharmaceutical composition in accordance with  claim 16 , wherein the composition is a chemotherapeutic agent. 
     
     
       19. The pharmaceutical composition in accordance with  claim 16 , wherein the composition is formulated in a therapeutic dosage by itself, in combination with at least one other pharmaceutical, or chemically linked to at least one other pharmaceutical. 
     
     
       20. The pharmaceutical composition in accordance with  claim 16 , wherein the composition is in combination with pharmaceutically acceptable carriers, diluents, stabilizers, solubilizers, lubricants, binders and the like or excipients thereof. 
     
     
       21. The pharmaceutical composition in accordance with  claim 16 , wherein the composition comprises a mammalian metabolic conjugate of the active ingredient compound. 
     
     
       22. The pharmaceutical composition in accordance with  claim 16 , wherein the medical conditions include, but are not limited to, cancer, inflammatory and infectious conditions, vasoreactive and vasoocclusive conditions, coronary and peripheral athlerosclerosis, parasitic diseases, neurologic and neuromuscular conditions, and viral conditions including AIDS. 
     
     
       23. The pharmaceutical composition in accordance with  claim 22 , wherein the medical conditions further include vasospasm, Parkinson's disease, Alzeihmer's disease, malaria, tuberculosis, arthritis, allergic and asthmatic conditions, hepatitis, coronary and peripheral vascular ischemia-reperfusion injury of blood vessels. 
     
     
       24. The pharmaceutical composition in accordance with  claim 16 , wherein the composition is orally formulated in combination with a liquid diluant or a solid carrier. 
     
     
       25. The pharmaceutical composition in accordance with  claim 16 , wherein the therapeutically effective dosage of the composition prevents the occurrence of, reduces the rate of growth of, or diminishes the size of tumor cells or any combination therof. 
     
     
       26. A pharmaceutical composition for treating and preventing medical conditions in mammals, the composition being capable of binding intracellular iron and comprising as active ingredient a compound of the formula:                    
       wherein: 
       X 1 , X 3 , and X 5  are N, O or S, wherein the X 1 , X 3 , and X 5  atoms are at the 1, 3, and 5 positions of a cyclohexyl group and are in a cis, cis disposition; and  
       s, s′, s″ are 1 to about 2;                    
       wherein: 
       R is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof that may or may not be identical in Z, Z′ and Z″;  
       Y is NH 2  or NHR′, OH, or SH, CO 2 H, P(O)(OH) 2 , R′P(O)OH, R′OP(O)OH groups, or any combination thereof, and R′ is H, aliphatic, branched aliphatic, or aryl groups, or any combination thereof, or Y is a group containing N, O, or S atoms that originate from either aliphatic, branched aliphatic, aryl, heterocyclic groups, or any combination thereof, in any case, Y and R′ may or may not be identical in Z, Z′ and Z″;  
       t is 1 to about 2; and  
       n is between 0 and about 3.  
     
     
       27. The pharmaceutical composition in accordance with  claim 26 , wherein the active ingredient compound is selected from the group of metal chelators consisting of tach-C(Me)pyr, tach-6-Mepyr, tachquin, (N—R) 3 tachpyr, tachpyr-H 2  tachpyr-2H 2  and tach-N-Me-Im-imine. 
     
     
       28. The pharmaceutical composition in accordance with  claim 26 , wherein the composition is a chemotherapeutic agent. 
     
     
       29. The pharmaceutical composition in accordance with  claim 26 , wherein the composition is formulated in a therapeutic dosage by itself, in combination with at least one other pharmaceutical, or chemically linked to at least one other pharmaceutical. 
     
     
       30. The pharmaceutical composition in accordance with  claim 26 , wherein the composition is in combination with pharmaceutically acceptable carriers, diluents, stabilizers, solubilizers, lubricants, binders and the like or excipients thereof. 
     
     
       31. The pharmaceutical composition in accordance with  claim 26 , wherein the composition comprises a mammalian metabolic conjugate of the active ingredient compound. 
     
     
       32. The pharmaceutical composition in accordance with  claim 26 , wherein the medical conditions include, but are not limited to, cancer, inflammatory and infectious conditions, vasoreactive and vasoocclusive conditions, coronary and peripheral athlerosclerosis, parasitic diseases, neurologic and neuromuscular conditions, and viral conditions including AIDS. 
     
     
       33. The pharmaceutical composition in accordance with  claim 32 , wherein the medical conditions further include vasospasm, Parkinson's disease, Alzeihmer's disease, malaria, tuberculosis, arthritis, allergic and asthmatic conditions, hepatitis, coronary and peripheral vascular ischemia-reperfusion injury of blood vessels. 
     
     
       34. The pharmaceutical composition in accordance with  claim 26 , wherein the composition is orally formulated in combination with a liquid diluant or a solid carrier. 
     
     
       35. The pharmaceutical composition in accordance with  claim 26 , wherein the therapeutically effective dosage of the composition prevents the occurrence of, reduces the rate of growth of, or diminishes the size of tumor cells or any combination therof.